TWI296525B - Novel combination of nonsedating antihistamines with substances which influence leukotriene action, for the treatment of rhinitis/conjunctivitis - Google Patents

Description

Ministry of Economy, Ministry of Intellectual Property, Staff Consumer Cooperatives, Printing 1296525 A7 B7 V. INSTRUCTION DESCRIPTION (1) TECHNICAL FIELD The present invention relates to a novel pharmaceutical composition comprising an antihistamine having no sedative effect and an effect white A triene-acting substance which may be a leukotriene D 4 antagonist, a 5-lipoxygenase inhibitor, or a 5-lipoxygenase-activated protein (FLAP) antagonist. These compositions are suitable for the treatment of topical treatments such as allergic and/or vasomotor rhinitis or allergic conjunctivitis. Antihistamines require rapid removal of acute symptoms characterized by redness, itching or swelling, while inflammatory agents lurking under symptoms successfully deliver leukotriene antagonists contained in the composition. It is controlled. Previously, the number of people with allergic disorders worldwide has increased dramatically. Studies have shown that an average of 7.5 percent of all children and adolescents in the world suffer from rhinoconjunctivitis (hyperthermia and ocular symptoms) (asthma, allergic rhinitis) Worldwide variation in the prevalence of conjunctivitis and atopic eczema: ISAAC, Lancet, 351, 1 225- 1 332, 1 998). In Western Europe, the prevalence of approximately 14% is clearly higher ( Annesi-Maesano, I. and Oryszczyn, MP: Rhinitis in adolescent s, Results of the ISAAC survey, Revue Francaise d'Allergologie et d'lmmunologie Clinique , 38, 283-289, 1998; Norrman, E., L. Nystrom, E. Jonsson and N. Stjernberg: Prevalence and incidence of asthma and rhinoconjunctivitis in Swedish teenagers, European an Journal of Allergy and Clinical Immunology, 53, 28-35, 1998). This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 7^ I-------ί------IT------^ (Please read the back Precautions Please fill out this page again) 1296525 A7 __ B7 _ V. INSTRUCTIONS (2) The extensive research activities in recent years have led to the recognition that allergic rhinoconjunctivitis is an inflammatory process in terms of persistent inflammation. Although histamine is still considered to be the most important mediator in the early stages of the following symptoms and is considered to be the most important trigger for symptoms (such as reddening, sneezing, itching, and excessive secretion (runny nose and Tears), however, further intermediaries are involved in nasal obstruction, secretion, and have been involved in the progression of inflammation (eg, attraction of primary inflammatory cells, enhancement of cell infiltration, etc.). Therefore, the subject of treatment has been transferred from symptomatic treatment to extra Anti-inflammatory treatment, the latter affects the inflammation underlying allergic disorders. Histamine and leukotrienes are released in the early and late stages of allergies. Acute symptoms of nasal conjunctivitis (itching, redness, Swelling, runny nose and flow can be easily controlled by, among other things, the first and second generations of classical antihistamines. However, they have little therapeutic and pertinent influence on the inflammation underlying the disorder. And their role is always gradual, usually, allergic rhinitis (nasal conjunctivitis) is considered by the patient and the physician to be insignificant, due to There is not enough treatment. Therefore, the so-called stage change occurs, that is, bronchial asthma, which is considered to be very serious, is developed from relatively harmless rhinitis. For this reason, it is impossible to omit even Allergic rhinoconjunctivitis should be treated adequately and strongly. Only then, the patient can then live under the symptoms, and then, the phase changes (which under certain conditions are life-threatening) can be prevented. Many animal experiments and clinical studies have indicated that histamine and LTS can be detected in nasal secretions (Yamasaki, UTMatsumoto, S. Fuku da, T. This paper scale applies to National Standards (CNS) A4 specifications (210 X 297 mm) _ (Please read the note on the back and fill out this page) 1296525 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Inventions (3) Natayama, H. Nagaya, Y. Ashida. Involvement Of thromboxane A2 and histamine in experimental allergic rhinitis of guinea pigs. J. Pharmacol. Exp. Ther. 82:1046, 1 997; Pipkorn, UG Karlsson, L Enerbeck. Cellular resp Onse .of the human allergic nasal mucosa to natural allergen exposure. J. Allergy Clin. Immunol. 3 5:234, 1 988; Volovitz, B., SL Osur, M. Berstein, PL Ogra. Leukotriene C4 release in upper respiratory mucosa During natural exposure to ragweed-sensitive children. J. A .l 1 ergy C1 i η · I mmun 01. 8 2:4 1 4,1 9 8 8 ). Because histamine H 1 receptors are blocked, certain symptoms such as sneezing, redness, itching, and intranasal or intraocular hypersecretion (runny, tearing) are significantly reduced (Simons, FER, KJSimons. Second) Generation H1 -receptor antagonists. Ann. Allergy 66··5,1991 ). In the acute phase of allergic reactions. Regardless of whether it is local or not, the granule action or depletion of intracellular storage of mast cells or sputum granulocytes is prominent. This phenomenon is a process controlled by extracellular or intracellular calcium. Histamine, however, is not only an intermediary for causing allergic symptoms, it also acts on allergic inflammation by affecting the release of cellular activity. Studies on human conjunctival epithelial cells (eyes) showed that histamine significantly increased I 1-8 and G Μ - C S F (granulocyte macrophage population stimulating factor). This release can be prevented by the histamine H i receptor antagonist, ie the effect is mediated by the Η 1 receptor (w.eirner, LK, DA Gamache, J. Μ. Yanni. Histamine-stimulated cytokine) The scale applies to China National Standard (CNS) A4 specification (210X297 mm) ' ' One - (Please read the back note first and then fill this page) 1296525 A7 B7 Economy, Ministry of Intellectual Property Bureau employee consumption cooperative printing 5, invention Description (4) secretion from human conjunctival epithelial cells: inhibition by histamine Hi-antagonist emedastine. Int.

Arch. Allergy Immunol. 115:288, 1998). In addition, it is known that allergic stimuli not only release the histamine stored in the cells from the fat cells, but also cause other intermediate mediators, such as leukotrienes, to re-synthesize. The leukotrienes are intermediaries belonging to the group of arachidic acid derivatives. They are acid derivatives, and arachidic acid is a fatty acid which is a component of membrane phospholipids. The leukotrienes are formed by arachidic acid via the catalytic action of 5-lipoxygenase (5 - L 0 X ). At present, only the pathogenic role of the so-called cysteamine decyl-leukotrienes belonging to LTC4, LTD 4 and LTE 4 has been confirmed. The role of leukotrienes may be due to the occupation of their receptors or by their The synthesis is inhibited and occurs. In addition to inhibition of 5-lipoxygenase, inhibition of 5-lipoxygenase-activated protein (F L A P ) can also cause synthesis of leukotrienes. Among many L T antagonist antibodies, several purine antibodies, such as zafirlukast, montelukast, pranlukast, etc., are used to treat bronchial asthma. Among a variety of 5-L X inhibitors, zileuton is available. The so-called F L A P inhibitors include, for example, Μ K - 591, Bay X 1005, both of which are still in the clinical trial period. A variety of studies have confirmed the importance of leukotrienes in allergic disorders. Thus, after sputum allergen challenge, the LT concentration in the nasal washout of patients with allergic rhinitis was significantly increased in the early and late stages (Creticos, PS, SP Peters, NF Adkinson. Peptide leukotriene release after antigen challenge) In patients This paper size applies to the Chinese National Standard (cns) a4 specification (21 ox297 mm) (please read the notes on the back and fill out this page)

1296525 A7 B7 V. INSTRUCTIONS (5) sensitive to ragweed0 (Please read the note on the back and then fill out this page) N.Eng. J. Med· 3 10:1 626,1 984). Cysteamine thiol-L T s can induce excessive secretion (runny nose or tearing), but leucotrienes appear to be far more important in nasal obstruction. The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed the histamine-induced nasal obstruction in the early stage of allergic reactions, but only lasted for a few minutes. However, the infarction induced by leukotrienes was delayed to the late stage. Observed, and after allergic challenge, lasted 6-8 hours. Compared to histamine, sneezing and reddening do not occur after LT excitation (〇kuda, M., T. Watase, A. Mazewa, CM Liu. The role of leukotrine D4 in allergic rhinitis. Ann. Allergy 60 : 5 3 7,1 9 8 8 ). However, when 俟 is stimulated by LTD 4, there is a long-lasting infiltration of eosinophils, and the largest part of the sputum granulocytes is allergic to inflammation (Fujika, M. et al., see before ). These so-called late reactions (such as nasal infarction) can be LT antagonists, such as zafirlukast (Donnelly, AL, M. Glass, Μ.C. Minkwitz, TB C as ale. The leukotriene D4-receptor antagonist ICI 2042 1 9 Relief symptoms of acute seasonal allergic rhinitis. Am. J. Resp. Crit. Care Med. 151:1734, 1995) (ICI 2042 1 9 = Zafirlukast). 5 — L〇X inhibitors can also significantly reduce allergic reactions not only in animal experiments but also in human therapy (Liu, MC, LM Dube, J. Lancaster, and the zileuton study group. Acute and chronic Effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J. Allergy Clin. Immunol. 98:85 9,1996) 0 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) Two _ 1296525 A7 B7 V. Description of invention (6 ) (Please read the notes on the back and fill out this page.) Among the antihistamines, Azelastine is currently available in systemic (stings) and topical (nose) The only active ingredient used in internal spraying and eye drops. Therefore, even patients with non-strong and well-defined allergic symptoms can be successfully treated. Due to the various medicinal compositions, the patient can be treated with azelastine depending on the nature and severity of the symptoms, so inflammation underlying the disorder can be suppressed. Among the most recent antihistamines, A ze 1 astine is the first dose or concentration according to its therapeutic considerations, and its synthesis inhibits the synthesis of leukotrienes that play an important role in allergic inflammation. Tuckermann, U., Th. Simmet, W. Luck, I. Szelenyi, BA Peskar. Inhibition of cysteinyl-leukotriene production by aselastine and its biological significance. Agents and Actions 24:217, 1988). Azelastine's anti-white triad effect is also detected in controlled clinical trials in allergies. (Shin, Μ.Η., FM Baroody, D. Proud, A. Kagey-Sobotka, LM Lichtenstein, M. Naclerio. The effect of azelastine on the early allergic response. Clin. Exp.Allergy 22:289,1 992 ) ° Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Due to this reaction, the clinical efficiency of azelastine (it can be compared with budesonide, a glucocorticoid) can also be explained (Wang, DY, Smitz, M. De Waele, P Clement. Effect of topical applications of budesonide and azelastine on nasal symptoms, eosinophi 1 counts and mediator release in atopic patients after nasal allergen challenge during the pollen season. Int.

Arch. Allergy Immunol. 1 1 4:1 85, 1 997; Gastpar, H., R. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296525 A7 B7 V. Description of invention (7 (Please read the notes on the back and fill out this page)

Aurich, U. Petzold. Intranasal treatment of perennial rhinitis:Comparison of azelastine nasal spray and budesonide nasal aerosol. Arzn. Forsch. -Drug Res. 43:475, 1993)〇A zel as tine inhibits LT synthesis and the mechanism of LT release It is unique and has not been mentioned in other antihistamines. As is well known, many of the release processes are carried out via an increase in the level of intracellular Ca2+, and an increase in the level of Ca2+ in the cells occurs due to allergic stimulation of the organelle cells. a 2 + initiates the determinant step of leukotriene synthesis and release enhancement. A z e 1 a s t i n e inhibition release (T a k a n a k a, K.

Effects of azelastine on polymorphonuclear leukocytes: arachidonate cascade inhibition mechanism. Progress Med. 275, 1987; Chand, N., et al. Inhibition of allergic and non-allergic leukotriene formation and histamine secretion by azelastine:Implication for its mechanism of action. . Economy, Ministry of Intellectual Property, employee consumption cooperative printing

Arch. Allergy Appl. Immunol. 90:67, 1989; Senn, N., et al. Action of azelastine on intracellular Ca2+ in cultured airway smooth muscle. Eur. J. Pharmacol. 205:29, 1991; Chand, N., RD Sofia. A. novel in vivo inhibitor of leukotriene biosynthesis: A possible mechanism of action: A mini review. J. Asthm. 3 2:227, 1995) o The action of LT receptor antagonists; As receptor antagonists, they have to occupy the L T receptor. Thus, the released leukotrienes are accessible to their receptors and exhibit their ability to act as receptors. This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X297 mm) _ _ 1〇: ' A 1296525 A7 B7 V. Description of invention (8) Composition for application in the nose, which contains leukotrienes An inhibitory property of histamine, as well as glucocorticoids, and, if appropriate, decongestants, anti-allergic agents, dissolved mucilage agents, non-opioid-type pain relievers, lipoxygenase inhibitors, and leukotriene receptors Antagonists are disclosed in EP 0 7 8 0 1 2 7 A 1 and are recommended for the treatment of allergic rhinoconjunctivitis. The cooperation between antihistamine and glucocorticoids must increase the effectiveness of the treatment. In the case of topical treatment of rhinitis, WO 98/48839 also discloses glucocorticoid-type anti-inflammatory agents which are added to the anti-inflammatory agent for the purpose of increasing efficiency, for example, at least one vasoconstrictor, a leukotriene An inhibitor, a leukotriene inhibitor, an antihistamine, an anti-allergic agent, a decomposing mucilage agent, an anesthetic, an anticholinergic agent or a per willase inhibitor. As disclosed in W〇9 8 / 3 4 6 1 1 , the composition for topical treatment of allergic asthma is proposed to consist of the following components: deethoxycarbonyl loratadine (a type without sedative effect) a metabolite of the antihistamine loratidine) and a leukotriene antagonist (which may be a leukotriene D 4 antagonist) a 5-lipid oxidation inhibitor or a FLAP antagonist . Deethoxylated lolatazide must avoid the many adverse side effects of lolatazide and other antihistamines without sedative effects. A. Roquet et al. in "Combined antagonism of leukotrienes and Histamine production dominant inhibition of allergen -induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med., 1997,155; National Standard (CNS) A4 Specification (210X297 mm) (Please read the note on the back and fill out this page) Customs Guangbian Intellectual Property Office Staff Consumer Cooperative Printed 1296525 A7 B7 ---;~—-- - V. Description of the invention (9) (Please read the notes on the back and fill out this page) 1 8 5 6 · 1 8 6 3 ” In the article, study Lola D (1 oratadine), Bai San Chuan The anti-drug zafirlukast and a combination of the above two active ingredients are orally administered to an allergen-induced asthmatic airway disorder. Merck & Co., W 〇 9 7 / 2 8 7 9 7 study, oral or parenteral injection of lorazidine and five selected white scented anti-drugs, ie, Monetlukast, zafirlukast, pronlukast, 1 one (((R) — 3 — (2 — (6,7 — a gas base — 2 — wow), ethyl) phenyl)—3— (2 — (. 2- Sodium hydroxy-2-hydroxy)phenyl- phenyl)methyl)cyclopropaneacetate, 1 -((1(1R)~3 -(2 - (2,3 -dichlorothienyl)[3,2 — b]pyridine-5-yl)-(E)-ethylidene)phenyl)-3(2-(1~-yl-1-1-methylethyl)phenyl)-propyl)thio) Methyl)cyclopropaneacetic acid is used to treat asthma, allergies and inflammation. In the treatment of allergic rhinitis/conjunctivitis, a composition with high efficacy and safety is further developed because of the many side effects caused by the introduced preparation, lack of treatment success, and non-specific treatment in some occasions. Highly needed. Printed by the Economic/Ministry of Intellectual Property Office Staff Consumer Cooperatives The present invention and the present invention are based on the discovery and production of novel compositions for the treatment of allergic rhinitis/conjunctivitis. DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition which can be administered orally or topically to treat allergic and/or vasomotor rhinitis or allergic conjunctivitis, and such compositions contain an effective amount 1 does not carry the paper size. Applicable to China National Standard (CNS) A4 specification (210X297 mm) ~ _ 1296525 A7 B7 V. Invention description (1彳) (Please read the note on the back and fill in this page) Dosage type: 1 antihistamine without sedative effect (except for 1〇ratadine type antihistamine) ' should be azelastine, but, for example, levocabastme, cetirizine, fexofenadine, mizolastine, astemizole, also Suitable, and 2 leukotrienes 舍4 inhibitors that affect the action of leukotrienes', for example, 11101^111]^51:,2&^]:111]^51: or pranlukast, or 3 a 5-fat An oxidation inhibitor, such as z丨1 eut 〇n, pirip 〇st or AWD 23-115 or 4 a FLAP antagonist, such as Μ K — 5 9 1 , Μ K 8.8 6 6, B ayx 1 〇〇 5, Dosage type for simple local or oral administration For example, in a spray-type or drip type or the like type of pastilles dosage form. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, in accordance with the present invention, the novel compositions consisting of the following ingredients can be applied to each other simultaneously or sequentially, in a fixed composition form, or in a separate substance. Intra or intraocular) or oral administration: 1 an antihistamine (except for the loratadine antihistamine), preferably azelastine, but '·example ' ' levocabastine, cetirizine, fexofenadine, mizolastine, astemizole also And 2, a white susceptibility D 4 antagonist that affects the action of leukotrienes, such as montelukast, zafirlukast or pra η 1 ukast or 3 a lipoxygenase inhibitor, such as zi 1 eut ο η, pipipost or AMD 2 3 - 1 1 5 or 4 An F LA P antagonist, such as MK-591, MK-886 or Bayxl005, which may be present in the form of a pharmaceutically acceptable salt thereof. In the case where the respective compositions are present, the compositions are modified such that the individual active ingredients contained in the dosage unit are the same as the individual active ingredients may be present in the composition. The amount of this paper is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1296525 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (12) Individual active ingredients in individual blending The weight ratio in the product is the weight ratio relative to the individual ingredients that may be present in the composition. The result of the combination not only acts quickly, but also achieves high therapeutic efficiency, and is accompanied by a strong anti-inflammatory effect. The action mode between the above active ingredients is complementary and also operates in a similar pharmacokinetic manner. The long period of action allows the patient to take twice a day. If the active ingredient is present in a fixed composition form, the patient is more likely to be administered, and the cap active ingredient is contained in a single tablet or in a single container. According to the present invention, the concentration of the antihistamine component may range from 0.01% to 0.5% by weight of the leukotriene antagonist in the composition may range from 0. 01% to 5%. between. The suitable concentration of the antihistamine component is from 0. 05% to 0. 2%, and the leukotriene antagonist is from 0.5 to 5%. The dosage can be administered once or twice a day, and the individual dose of antihistamine should be 50-500//g, preferably 20 0-40 0 //g for local administration. The dose of the leukotriene D 4 antagonist is between 100 and 2000/g, preferably between 200 and 1000 //g. 5 — The L〇X or F L A P inhibitor is administered at a dose ranging from 50 to 2 0 0 // g, preferably from 2 0 0 to 1 0 0 // g. The dose of the antihistamine (e.g., azelastine) is between 0.5 and 16 m g / day, preferably 2 - 8 m g / 曰. In the case of a white D 4 inhibitor (e.g., m ο n t e 1 u k a s t), the individual dose is from 1 to 5 mg/曰, preferably from 5 to 10 mg/曰. 5 — L〇X inhibitors, such as zileuton, are given in an oral dose of 1–6. The paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm) _ 15_ (Please read the back note first and then fill out this page) 1296525 Α7 Β7 V. Description of invention (14) (Please read the precautions on the back and fill out this page.) For anti-corrosion purposes, a combination of sodium edetate and benzylammonium chloride should be used. The concentration of sodium edetate used is 〇· 0 5 · 0 · 1%, and the application concentration of benzylammonium chloride is 〇· 〇〇5 -〇· 0 5 % 〇 is suitable for adjusting the osmotic pressure 'weight A suitable adjuvant for osmolality, sodium chloride, potassium chloride, mannitol 'glucose' sorbitol, glycerol or ethylene glycol, etc. may be used at a concentration of about 1 to 1% by weight. Contains thickeners, 俾 increases viscosity' and thus prolongs and improves the contact between drugs and human tissues. These thickeners include methylcellulose, hydroxymethyl·propylcellulose, hydroxyethylcellulose, carboxymethyl Cellulose sodium, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylate, polyacrylamide, dextrin, gellan gum, poloxamer or cellulose acetate phthalate . Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, and the composition of the present invention comprises a pharmaceutically acceptable buffer which is capable of adjusting ρ Η to maintain between about 4 and 8 (to 5 · 5 to 7 · 5 As a principle, this type of buffer is citrate, phosphate, 2-amino-2-hydroxyindole-1,3-propanediol, glycine, boric acid, sodium tetraborate, acetic acid and acetic acid. sodium. Further, further adjuvants such as hydrochloric acid or sodium hydroxide can be used to adjust ρ Η ° The invention will be illustrated by way of certain examples. Example 1 This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1296525 A7 B7 V. Description of invention (15) Nasal spray J or nasal drop containing azelastine hydrochloride hydrochloride (〇·1%) liquid. CPlease read the notes on the back and fill in the tribute]

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Azelastine hydrochloride O.lOOOOg Hydroxypropyl methylcellulose O.lOOg Sodium ethylenediaminetetraacetate 0.0500g Ammonium chloride ammonium nitrate 0.0125g One sodium hydroxide qs ph[sic]6.0 Sorbitol 70% 6.6666 g A pure water is added to 100 m 1 _ Economy, Ministry of Intellectual Property's staff consumption cooperative printing solution modulation: About 45 kg of pure water is introduced into a container with a stirrer. Ingredients, hydroxypropyl·methylcellulose 'ethyl methoxide sodium acetate, benzalkonium chloride and sorbitol, dissolved under stirring Μ into pure water to make the total amount of solution reached 4 9 · 5 liters, Adjust the ρ Η値 of this solution to 6 · 0 using a 1 Ν N a 〇Η solution. Use pure water to make the total amount of 50 ° 0 liters and stir. The solution was filtered through a membrane filter having an orifice size of 0 · 2 // m, and the filtrate was dispensed into the bottle. Example 2: . Nasal spray or nasal drop suspension containing montelukast (1%). This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296525 A7 B7 V. Invention description (16)

Montelukast l.OOOOg Avicel RC 591 l.lOOOOg Polysorbate 80 O.lOOOg Sorbitol solution 70% 6.0000g Sodium ethylenediaminetetraacetate 0.0500g Benzammonium chloride 0.0200g Pure water added to 100ml (Please read the back Note: Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed: Introduce 4 5 kg of water into a container with a stirrer and a homogenizer, and homogenize Ari cel RC in the container based on high speed. 591. Then, under stirring, the substance poilysorbate 80, sorbitol solution, sodium edetate and benzalkonium chloride are dissolved. The active ingredient m ο n t e 1 u k a s t is then homogenized at a high speed until a homogeneous suspension is formed. Then, pure water was added to make a final capacity of 50 liters and further homogenized. The suspension is evacuated to remove the resulting air bubbles. The resulting suspension is then dispensed into a bottle. Example 3: Nasal spray or nasal drops containing azelastine hydrochloride (0.1%, dissolved) and montelukas t (1%, suspension). This paper size applies to the national standard (CNS) A4 specification (210 X 297 mm) ~ ' 1296525 A7 B7 V. Description of invention (17) Montelukast l.OOOOg Azelastine hydrochloride O.lOOgg Avicel RC 591 l.lOOOOg Polysorbate 80 O.lOOOOg Sorbitol 70% 6.0000g Sodium ethylenediaminetetraacetate 0.0500g Benzalkonium chloride 0.0200g Pure water. Add to 100ml (please read the back note before you fill out this page) Economy, Ministry Printed by the Intellectual Property Office Staff Consumer Cooperative: Introduce 4 5 kg of pure water into a suitable container with a stirrer and a homogenizer, and homogenize the Avicel RC 591 in the container. Then, the active compound azelastine hydrochloride and the adjuvant P〇lysorbau 80, sorbitol solution, sodium edetate and benzylammonium chloride are dissolved in sequence. The active ingredient montelukast is then homogenized at high speed until a homogeneous suspension is formed. Pure water was then added to bring the final capacity to 50 liters and homogenized again. The suspension is then evacuated to remove the resulting air bubbles. The resulting suspension is then dispensed into the bottle. The spectrum of action of certain antihistamines and L T antagonists or 5 - L Ο X and F L A P inhibitors can lead to the conclusion that the combination of two substances exhibits a synergistic effect on allergic rhinoconjunctivitis. The following pharmacological studies describe az e 1 as ti ne and m ο n te 1 u ka st on their own or . This paper scale applies to the National Standard of the Week (CNS) A4 size (210X297 mm) -20- 1296525 A7 B7 , invention instructions (18) (please read the precautions on the back and then fill out this page) Combination method, according to the rhinitis model, the role of the brown Nawei rats, take brown Nawei rats, by the egg albumin and hydrogen The suspension of alumina suspended in physiological saline was subjected to double intraperitoneal injection for two consecutive days to be automatically sensitized. Three weeks after sensitization, a cannula was taken, and under the anesthesia of thiopental, the cannula was inserted into the trachea of the animal in a straight walking manner to maintain the breathing of the animal, and another cannula was taken. In retrograde mode, it is advanced through the trachea to the internal orifice of the posterior nasal orifice to allow perfusion of the nasal cavity and fixation. The nasal perfusate can drip out through the nasal cavity and can be received by a grading collector. The test substance was suspended in Tylose (monteluckast) or dissolved in physiological saline (a z e 1 a s t i n e ) and injected into the peritoneum 60 minutes before the allergen was activated. In order to wash the mucus off the nose, a roller pump was used to perfuse the P B S through the nasal cavity for 30 minutes (irrigation rate of 0.5 m 1 / m i η ). In the case of topical application, the test substance is added to the perfusate at a molar concentration, and the solution is perfused through the nose 30 minutes before the allergen is activated. Then, the plasma indicator Evans Blue (1 / animal, dissolved in P B S and 1% strong economy, the Ministry of Intellectual Property's employee consumption cooperative printing solution) was injected into the jugular vein. There is a 15 minute interruption period during which the perfusate is collected. Then, the albumin PBS solution (10 mg / 2 egg albumin in PBS) was perfused into the nasal cavity for 6 minutes to achieve the allergic action. During the perfusion, the perfusate was collected in the fraction collector. A grading collection time is taken every 15 minutes. The total number of gradings collected for the sample was 5. The sample was centrifuged and placed on a microtiter piece and measured using a Digiscan luminometer at a wavelength of 6 20 n m. The blank is automatically deducted and is calculated using the A U C program. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 1296525 A 7 _ B7 _ V. Description of the invention (19) Minutes. The effect of the substance in the formulation group was calculated as % versus the vehicle control group. The increased mucosal permeability exhibited by allergens will be assessed by the release of messengers (eg, histamine and leukotrienes), which will occur even in allergic individuals after exposure to the antigen. Occurs, and is marked by increased fluid secretion and nasal infarction. (Please read the note on the back and then fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies to China National Standard (CNS) A4 Specification (210X297 mm) 1296525 A7 ____ B7 _ V. Invention Description ( 20) Table 1 azelastine and montelukast in a separate and combined manner (peritoneal 'injection), in the active sensitized and locally stimulated brown Nawei rats, the effect of nasal mucosal permeability (mg /kg.,ip) Inhibition in %Azelastine 0.01 11 0.1 39 0.3 42 1 47 Montelukast 0.1 7 1 26 3 39 10 44 30 58 Azelastine 0.01 + + 40* montelukast 0.1 * ρ<0.05 ------- -- Clothing -- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed separately 0 · 0 1 mg / kg intraperitoneal injection (i · Ρ . ) dose of aze 1 astine, resulting in a small inhibition rate of vascular permeability of 1 1%. When m ο n t e 1 u k a s t was administered at a dose of 0 · 1 m g / k g i · p · , a slight activity of 7% inhibition was also exhibited. And azelastine is applied to this paper scale. National Standard (CNS) A4 specification (210X297 mm) h ' 1296525 A7 B7 V. Description of invention (21) 0 · 0 lmg/kg i. ρ · dose and montelukast When the dose of 0.1 mg / kgi · p · is combined, it will cause 4% 受% of the mucosal plasma extravasation (ρ < 〇· 〇 5 ). F L A P inhibitor B A Y X 1 0 0 5 to 〇 · 1 m g /

The dose of k g 1 · P . inhibited mucosal permeability by 31%. AWD 2 3 - 1 1 5 (a 5 - L〇X inhibitor), dose-dependent inhibition of vascular permeability in the dose range of 0 · 0 3 to 1 〇 mg / kg (3 7 - 5 4 % ). (Please read the notes on the back and then fill out this page) ^^衣.

1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1296525

A B7 V. Description of invention (22) Table 2: azel a stine and A WD 23-115 in a single force and combination (local application to perfusate: brown Nawei rats, double 1 >, subject to automatic Sexual sensitization and local stimulating effect of nasal mucosal permeability (# mol/1) Inhibition in % A ze 1 astine 0.003 3 0.01 40 0.03 60 A WD 23-115 0.1 12 0.3 32 1 49 Azelastine + AWD 23-115 0.003 + 0.1 31* *ρ<0·05 (Please read the note on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on topical application, histamine Η 1 blocked The agent aze 1 a st in e, that is, at a low concentration of .0.0 03 to 0.03 #111〇1/1, still exhibits a strong inhibitory effect on mucosal plasma extravasation. 5 - L〇X inhibitor AWD 2 3 - 1 1 5 At a concentration of 0 · 3 and 1 # m ο 1 / 1, the vascular permeability inhibition rate of 3 2 % and 49 %, respectively, is shown in a dose-dependent manner. If azelastine is 0 · 0 03 #mol /l concentration and AWD 2 3 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X297) PCT) 1296525 A7 B7 V. Inventive Note (23) -1 1 5 (0 · 1 // mol/ι ) When combined, the inhibition rate of mucosal extravasation is 31% ( P < 〇 · 0 5). (Please read the notes on the back and fill out this page)

1T Economics Department Intellectual Property Bureau Staff Consumer Cooperative Printed Paper Size Applicable to China National Standard (CNS) A4 Specification (210X297 mm) 1296525 η Attachment · · 90103054 Patent Application Chinese Qiaoqiao Book Revision Page Announcement — Application for the period of February 12, 1990, Case No. 90103054 (The above columns are filled by this Council) The Republic of China 96 years Μ 23曰 is the year of the month g ~ α —_· —. Completion Α 4 C4 Invention Salary Patent Specification Chinese : Xi Zuo invention new name English

Novel combination of nonsedating antihistamines with substii which influence leukotriene action, for the treatment of rhinitis/conjunctivitis_ nee Name (1) Hildjard Pappe, Hildegard C2) Junggenger Engel, Jurgen (2) Finster to Rielny Szelenyi , Istvan (1) Germany 0 Germany (3) German nationality invention creation > Residence, residence (1) Kieler Str* 6, D-01109 Dresden, Germany (2) Jasonno Enrion Road, Germany No.3 Erlenveg 3, D-63755 Alzenau, Germany (3) Handelstrasse 32, D-90571 Schwaig, Germany, Schwag, Germany, Schwarz, Germany

(1) Meda Pharmaceutical Co., Ltd. Meda Pharma GmbH & Co* KG Ministry of Economic Affairs Intellectual Property Office Staff Consumption ^-Society Printing III, Applicant Line Nationality Residence, Residence (Company) Representative Name (1) Germany (1) Benzstrasse 1, 100352 Bad Homburg, Baden-Württemberg, Germany (1)M Syugen Klopp Kromp, Hans-Jurgen Giandler Endler, G·

1296525 Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs Annex 2: Patent No. 90103054! Chinese manual replacement page Republic of China January 1997 | 3 BMjL · V, invention description (1 ()) Static action of antihistamine (except loratadine type antihistamine), should be azelastine, but, for example, , levocabastine, cetirizine, fexofenadine, mizolastine, astemizole, also suitable, and 2 leukotriene D 4 antagonists that affect leukotrienes, such as montelukast, • zafirlukast or pranlukast or 35-lipoxygenase inhibitors, for example Zileuton,piripost or AMD 2 3 — 1 1 5 ( 1 —[ 4 -( D-quinolin-2-yl-methoxy); yl]-5-methoxy- 1 Η — Oral azole — 3 —Alcohol a dihydrochloride or a F LAP antagonist, such as Μ Κ 591, ΜΚ 886, Ray x 〇 05, and, if appropriate, further pharmaceutically acceptable excipients and/or extenders or The present invention further relates to a method for preventing and/or treating allergic and/or vasomotor rhinitis or allergic conjunctivitis in a mammal, the method comprising a topical or oral administration of an effective amount of one of the following components Composition: 1 an antihistamine without sedative effect (except loratadine type antihistamine), preferably azelastne, but, for example, levocabastine, cetirizine, fexofenadine, mizolastine, astemizole, also Suitable, and a white triterpenoid D 4 antagonist that affects the role of the white scorpion, such as montelukast, zafirlukas t or pra η 1 ukast or 3 a 5-lipoxygenase inhibitor, such as zi 1 eut ο n , pil·ipost or AMD23·115 or 4 a FLAP antagonist, such as MK-591, MK-886, Bayxl® 5. The administration can be carried out simultaneously, sequentially or in an individual manner. The invention further relates to the following composition The appropriate paper size for the composition is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

-13- 1296525 Attachment 2 : 90103054 Chinese manual replacement page __ Republic of China 97 years and application: . Sound Xiao ^ 1 for 3 days correction y 5, invention description (13) grams / day, preferably 0 · 6 — 2 grams / day. (Please read the precautions on the back and fill out this page.) In the case of FLAP inhibitors, the dose is 5 〇 - 200 mg / 曰, preferably 1 〇〇 - 50 Omg / 曰. Amines and whitening antagonist compounds, and methods for their preparation are known. The active compounds are pharmaceutically processed into compositions according to conventional standard methods, which are preferably antihistamines and leukotriene antagonists. Or, if appropriate, in admixture with excipients and/or extenders or adjuvants, and then converting the mixture so obtained or suitable dosage form. The active compound is administered orally or topically in the form of a mixture. The mixture contains, for pharmaceutical purposes, a pharmaceutical extender, adjuvant or excipient. The composition for oral administration or topical administration can be formulated into different, pharmaceutically acceptable dosage forms. For example, nasal sprays, nasal drops, eye drops, tablets, capsules or granules. The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, printed in addition to the active ingredients, the composition of the present invention can be One step contains a variety of typical pharmaceutical dosage form components, such as antimicrobial preservatives, penetrants, thickeners, adjuvants for p Η conditioning or buffer systems. Antimicrobial preservatives include, for example, chlorinated phthalic acid. Ammonium hydrocarbon, chlorinated/hexadecyl pyridinium bromide, chlorobutanol, chlorhexidine acetate, chlorhexidine hydrochloride, chlorhexidine digluconate, chlorocresol, For methyl monohydroxybenzoate, p-propyl paraben, phenoxyethanol, phenylmercuric salt, sorbic acid, sodium thiomersal, thiomersal, paper size applicable to Chinese national standard (CNS) ) A4 size (210X297 mm) -16-

Claims (1)

1296525 A8 B8 C8 D8 VI. Application for Patent Scope 1. Attachment 4A: Patent Application No. 90103054 Replacement of Chinese Patent Application (Please read the note on the back and fill in this page) January 3, 1997 Amendment 1 - A pharmaceutical composition for the treatment of allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis. The pharmaceutical composition comprises a fixed or free composition and is suitable for topical or oral administration, and contains the following ingredients: a) from 0.001% by weight to 0.5% by weight of the composition of azelastine or a pharmaceutically active salt thereof, b) of the composition 〇1% by weight to 5% by weight of one selected from the group consisting of A leukotriene antagonist or a pharmaceutically active salt thereof of montelukast and AWD 23-115, c) one or more conventional pharmaceutical carriers, extenders and adjuvants. 2. A pharmaceutical composition according to claim 1 of the patent application, which is present in a dosage form of a topical administration type. 3. A pharmaceutical composition according to claim 1 of the patent application, which is present in an orally administered dosage form. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. 4 · For the pharmacy composition of the second paragraph of the patent application, the topical dosage form is a spray. 5. A pharmaceutical composition according to claim 2, wherein the topically administered dosage form is a nasal or ocular drop. This paper scale applies to China National Standard Rate (CNS) A4 specification (210X297 mm)